Fused bicycloheterocycle substituted quinuclidine derivatives

ABSTRACT

Compounds of formula (I)  
                 
 
wherein n is 0, 1, or 2; X is O, S, —NH—, and —N-alkyl-; Ar 1  is a 6-membered aromatic ring; and Ar 2  is a fused bicycloheterocycle. The compounds are useful in treating conditions or disorders prevented by or ameliorated by α7 nAChR ligands. Also disclosed are pharmaceutical compositions having compounds of formula (I) and methods for using such compounds and compositions.

TECHNICAL FIELD

The invention relates to fused bicycloheterocycle substitutedquinuclidine derivatives, compositions comprising such compounds, andmethods of treating conditions and disorders using such compounds andcompositions.

DESCRIPTION OF RELATED TECHNOLOGY

Nicotinic acetylcholine receptors (nAChRs) are widely distributedthroughout the central (CNS) and peripheral (PNS) nervous systems. Suchreceptors play an important role in regulating CNS function,particularly by modulating release of a wide range of neurotransmitters,including, but not necessarily limited to acetylcholine, norepinephrine,dopamine, serotonin and GABA. Consequently, nicotinic receptors mediatea very wide range of physiological effects, and have been targeted fortherapeutic treatment of disorders relating to cognitive function,learning and memory, neurodegeneration, pain and inflammation, psychosisand sensory gating, mood and emotion, among others.

Many subtypes of the nAChR exist in the CNS and periphery. Each subtypehas a different effect on regulating the overall physiological function.Typically, nAChRs are ion channels that are constructed from apentameric assembly of subunit proteins. At least 12 subunit proteins,α2-α10 and β2-β4, have been identified in neuronal tissue. Thesesubunits provide for a great variety of homomeric and heteromericcombinations that account for the diverse receptor subtypes. Forexample, the predominant receptor that is responsible for high affinitybinding of nicotine in brain tissue has composition (α4)₂(β2)₃ (the α4β2subtype), while another major population of receptors is comprised ofthe homomeric (α7)₅ (the α7 subtype).

Certain compounds, like the plant alkaloid nicotine, interact with allsubtypes of the nAChRs, accounting for the profound physiologicaleffects of this compound. While nicotine has been demonstrated to havemany beneficial properties, not all of the effects mediated by nicotineare desirable. For example, nicotine exerts gastrointestinal andcardiovascular side effects that interfere at therapeutic doses, and itsaddictive nature and acute toxicity are well-known. Ligands that areselective for interaction with only certain subtypes of the nAChR offerpotential for achieving beneficial therapeutic effects with an improvedmargin for safety.

The α7 nAChRs have been shown to play a significant role in enhancingcognitive function, including aspects of learning, memory and attention(Levin, E. D., J. Neurobiol. 53: 633-640, 2002). For example, α7 nAChRshave been linked to conditions and disorders related to attentiondeficit disorder, attention deficit hyperactivity disorder (ADHD),Alzheimer's disease (AD), mild cognitive impairment, senile dementia,dementia associated with Lewy bodies, dementia associated with Down'ssyndrome, AIDS dementia, Pick's Disease, as well as cognitive deficitsassociated with schizophrenia, among other systemic activities. Theactivity at the α7 nAChRs can be modified or regulated by theadministration of α7 nAChR ligands. The ligands can exhibit antagonist,agonist, partial agonist, or inverse agonist properties. Thus, α7ligands have potential in treatment of various cognitive disorders.

Although various classes of compounds demonstrating α7 nAChR-modulatingactivity exist, it would be beneficial to provide additional compoundsdemonstrating activity at the α7 nAChRs that can be incorporated intopharmaceutical compositions useful for therapeutic methods.Specifically, it would be beneficial to provide compounds that interactselectively with α7-containing neuronal nAChRs compared to othersubtypes.

SUMMARY OF THE INVENTION

The invention is directed to fused bicycloheterocycle substitutedquinuclidine compounds as well as compositions comprising suchcompounds, and method of using the same. Compounds of the invention havethe formula:

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,wherein:

n is 0, 1, or2;

X is selected from the group consisting of O, S, and NR¹;

Ar¹ is a 6-membered aromatic ring containing 0, 1, 2, 3, or 4 nitrogenatoms;

Ar² is a group of the formula:

Y¹ is independently selected from O, S, N(R²), and C(R³);

Y² and Y³ are each independently selected from the group consisting of Nand C(R ³);

R¹ and R² at each occurrence are each independently selected from thegroup consisting of hydrogen and alkyl;

R³ at each occurrence is independently selected from the groupconsisting of hydrogen, halogen, alkyl, aryl, —OR⁴, —NR⁵R⁶; and

R⁴ is selected from the group consisting of hydrogen, alkyl, aryl,alkylcarbonyl, and arylcarbonyl;

R⁵ and R⁶ at each occurrence are each independently selected from thegroup consisting of hydrogen, alkyl, aryl, alkylcarbonyl,alkoxycarbonyl, aryloxycarbonyl, and arylcarbonyl, provided that one ofR⁵ and R⁶ is hydrogen or alkyl.

Another aspect of the invention relates to pharmaceutical compositionscomprising compounds of the invention. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to nAChR activity, and more particularly α7 nAChRactivity.

Yet another aspect of the invention relates to a method of selectivelymodulating to nAChR activity, for example α7 nAChR activity. The methodis useful for treating and/or preventing conditions and disordersrelated to α7 nAChR activity modulation in mammals. More particularly,the method is useful for conditions and disorders related to attentiondeficit disorder, attention deficit hyperactivity disorder (ADHD),Alzheimer's disease (AD), mild cognitive impairment, senile dementia,AIDS dementia, Pick's Disease, dementia associated with Lewy bodies,dementia associated with Down's syndrome, amyotrophic lateral sclerosis,Huntington's disease, diminished CNS function associated with traumaticbrain injury, acute pain, post-surgical pain, chronic pain, inflammatorypain, neuropathic pain, infertility, need for new blood vessel growthassociated with wound healing, need for new blood vessel growthassociated with vascularization of skin grafts, and lack of circulation,more particularly circulation around a vascular occlusion, among othersystemic activities.

The compounds, compositions comprising the compounds, and methods fortreating or preventing conditions and disorders by administering thecompounds are further described herein.

DETAILED DESCRIPTION OF THE INVENTION

Definition of Terms

Certain terms as used in the specification are intended to refer to thefollowing definitions, as detailed below.

The term “acyl”, as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of acyl include, butare not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl,1-oxobutyl, and 1-oxopentyl.

The term “acyloxy”, as used herein, means an acyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of acyloxy include, but are not limited to,acetyloxy, propionyloxy, and isobutyryloxy.

The term “alkenyl”, as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy”, as used herein, means an alkyl group as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy”, as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkyl”, as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, and methoxymethyl.

The term “alkoxycarbonyl”, as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, represented by —C(O)—, as defined herein. Representativeexamples of alkoxycarbonyl include, but are not limited to,methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxyimino”, as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through an iminogroup, as defined herein. Representative examples of alkoxyiminoinclude, but are not limited to, ethoxy(imino)methyl andmethoxy(imino)methyl.

The term “alkoxysulfonyl”, as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl and propoxysulfonyl.

The term “alkyl”, as used herein, means a straight or branched chainhydrocarbon containing from 1 to 6 carbon atoms. Representative examplesof alkyl include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, and n-hexyl.

The term “alkylcarbonyl”, as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonyloxy”, as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylsulfonyl”, as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkylthio”, as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkynyl”, as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “amido”, as used herein, means an amino, alkylamino, ordialkylamino group appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples of amidoinclude, but are not limited to, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, and ethylmethylaminocarbonyl.

The term “aryl”, as used herein, means a monocyclic or bicyclic aromaticring system. Representative examples of aryl include, but are notlimited to, phenyl and naphthyl.

The aryl groups of this invention are substituted with 0, 1, 2, 3, 4, or5 substituents independently selected from acyl, acyloxy, alkenyl,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,alkoxysulfonyl, alkyl, alkylsulfonyl, alkynyl, amino, carboxy, cyano,formyl, haloalkoxy, haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto,nitro, thioalkoxy, —NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))alkoxy, (NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))sulfonyl.

The term “aryloxycarbonyl”, as used herein, means an aryl group, asdefined herein, or a benzyl group appended to the parent molecularmoiety through a carbonyl group, represented by —C(O)—, as definedherein. Representative examples of alkoxycarbonyl include, but are notlimited to, phenoxycarbonyl and benzyloxycarbonyl.

The term “arylsulfonyl”, as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a sulfonylgroup, as defined herein. Representative examples of arylsulfonylinclude, but are not limited to, phenylsulfonyl,(methylaminophenyl)sulfonyl, (dimethylaminophenyl)sulfonyl, and(naphthyl)sulfonyl.

The term “carbonyl”, as used herein, means a —C(O)— group.

The term “carboxy”, as used herein, means a —CO₂H group.

The term “cyano”, as used herein, means a —CN group.

The term “formyl”, as used herein, means a —C(O)H group.

The term “halo” or “halogen”, as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy”, as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl”, as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl” means an aromatic five- or six-membered ringcontaining 1, 2, 3, or 4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. The heteroaryl groups are connected to theparent molecular moiety through a carbon or nitrogen atom.Representative examples of heteroaryl include, but are not limited to,furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, and triazolyl.

The heteroaryl groups of the invention are substituted with 0, 1, 2, or3 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy,hydroxyalkyl, mercapto, nitro, —NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))alkoxy, (NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))sulfonyl.

The term “bicyclic heteroaryl” refers to fused aromatic nine- andten-membered bicyclic rings containing 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a tautomerthereof. The bicyclic heteroaryl groups are connected to the parentmolecular moiety through a carbon or nitrogen atom. Representativeexamples of bicyclic heteroaryl rings include, but are not limited to,indolyl, benzothiazolyl, benzofuranyl, isoquinolinyl, and quinolinyl.Bicyclic heteroaryl groups of the invention are substituted with 0, 1,2, or 3 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy,hydroxyalkyl, mercapto, nitro, —NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))alkoxy, (NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))sulfonyl.

The term “hydroxy”, as used herein, means an —OH group.

The term “hydroxyalkyl”, as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “mercapto”, as used herein, means a —SH group.

The term “nitro”, as used herein, means a —NO₂ group.

The term “—NR_(A)R_(B)”, as used herein, means two groups, R_(A) andR_(B), which are appended to the parent molecular moiety through anitrogen atom. R_(A) and R_(B) are each independently hydrogen, alkyl,alkylcarbonyl, or formyl. Representative examples of —NR_(A)R_(B)include, but are not limited to, amino, methylamino, acetylamino, andacetylmethylamino.

The term “(NR_(A)R_(B))alkyl”, as used herein, means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples of(NR_(A)R_(B))alkyl include, but are not limited to, (amino)methyl,(dimethylamino)methyl, and (ethylamino)methyl.

The term “(NR_(A)R_(B))alkoxy”, as used herein, means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough an alkoxy group, as defined herein. Representative examples of(NR_(A)R_(B))alkoxy include, but are not limited to, (amino)methoxy,(dimethylamino)methoxy, and (diethylamino)ethoxy.

The term “(NR_(A)R_(B))carbonyl”, as used herein, means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(A)R_(B))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “(NR_(A)R_(B))sulfonyl”, as used herein, means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NR_(A)R_(B))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl, and(ethylmethylamino)sulfonyl.

The term “sulfonyl”, as used herein, means a —S(O)₂— group.

The term “thioalkoxy”, as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of thioalkoxy include, but are no limited to,methylthio, ethylthio, and propylthio.

Although typically it may be recognized that an asterisk is used toindicate that the exact subunit composition of a receptor is uncertain,for example α3b4* indicates a receptor that contains the α3 and β4proteins in combination with other subunits, the term α7 as used hereinis intended to include receptors wherein the exact subunit compositionis both certain and uncertain. For example, as used herein α7 includeshomomeric (α7)₅ receptors and α7* receptors, which denote a nAChRcontaining at least one α7 subunit.

Compounds of the Invention

Compounds of the invention can have the formula (I) as described above.More particularly, compounds of formula (I) can include, but are notlimited to, compounds wherein Ar¹ is a group of the formula:

In a group of formula (b), X¹, X², X³, and X⁴ are each independentlyselected from the group consisting of N and —CR¹⁰, wherein R¹⁰ at eachoccurrence is independently selected from the group consisting ofhydrogen and alkyl. Preferably, at least one of X¹, X², X³, and X⁴ is—CR¹⁰, such that group of formula (b) contains 0, 1, 2, or 3 nitrogenatoms.

Specific examples of groups for Ar¹ are, for example,

Specific examples of groups for Ar² in a compound of formula (I) are,for example,

and the like.

Specific embodiments contemplated as part of the invention include, butare not limited to, compounds of formula (I), as defined, wherein:

3-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;

4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;

5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;

5-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-1H-indole;

6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;

2-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;

5-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indole;

4-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indole;

5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole;

5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-3-methyl-1H-indole;

5-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indole;

4-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indole;

5-{2-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indole;

5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-3-methyl- 1H-indazole;

6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1,3-benzothiazol-2-amine;

N-[4-(3-methyl-1H-indazol-5-yl)phenyl]quinuclidin-3-amine; orpharmaceutically acceptable salts, esters, amides, and prodrugs thereof.

Compound names are assigned by using AUTONOM naming software, which isprovided by MDL Information Systems GmbH (formerly known as BeilsteinInformationssysteme) of Frankfurt, Germany, and is part of the CHEMDRAW®ULTRA v. 6.0.2 software suite.

Compounds of the invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralelement. The terms “R” and “S” used herein are configurations as definedin IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The inventioncontemplates various stereoisomers and mixtures thereof and arespecifically included within the scope of this invention. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers. Individual stereoisomers of compounds of the inventionmay be prepared synthetically from commercially available startingmaterials which contain asymmetric or chiral centers or by preparationof racemic mixtures followed by resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Furniss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

Methods for Preparing Compounds of the Invention

As used in the descriptions of the schemes and the examples, certainabbreviations are intended to have the following meanings: Ac foracetyl; Bu for butyl; dba for dibenzylidene acetone; DEAD for diethylazodicarboxylate; DMSO for dimethylsulfoxide; EtOAc for ethyl acetate;EtOH for ethanol; Et₃N for triethylamine; Et₂O for diethyl ether; HPLCfor high pressure liquid chromatography; ^(i)Pr for isopropyl; Me formethyl; MeOH for methanol; NBS for N-bromosuccinimide; OAc for acetoxy;o-tol. for o-toluene; Ph for phenyl; t-Bu for tert-butyl; TFA fortrifluoroacetic acid; and THF for tetrahydrofuran.

The reactions exemplified in the schemes are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. The described transformations mayrequire modifying the order of the synthetic steps or selecting oneparticular process scheme over another in order to obtain a desiredcompound of the invention, depending on the functionality present on themolecule.

Nitrogen protecting groups can be used for protecting amine groupspresent in the described compounds. Such methods, and some suitablenitrogen protecting groups, are described in Greene and Wuts (ProtectiveGroups In Organic Synthesis, Wiley and Sons, 1999). For example,suitable nitrogen protecting groups include, but are not limited to,tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), acetyl,and trifluoracetyl. More particularly, the Boc protecting group may beremoved by treatment with an acid such as trifluoroacetic acid orhydrochloric acid. The Cbz and Bn protecting groups may be removed bycatalytic hydrogenation. The acetyl and trifluoracetyl protecting groupsmay be removed by a hydroxide ion.

The methods described below can entail use of various enantiomers. Wherethe stereochemistry is shown in the Schemes, it is intended forillustrative purposes only.

Quinuclidine ethers of general formula (8), wherein Ar¹ and Ar² are asdefined in formula (I), can be prepared as described in Scheme 1.3-Quinuclidinol of formula (1) is treated with a halophenyl iodide offormula (2), wherein X′ is bromide, chloride, or iodide, with Cul andCs₂CO₃ in 1,10-phenanthroline as described in Org. Lett., 2002, 4, 973,to obtain a halophenoxy quinuclidine of formula (4). Alternatively, acompound of formula can be obtained by treating 3-quinuclidinol with ahalo phenyl alcohol of formula (3), wherein X′ is bromide, chloride, oriodide, and diethyl azodicarboxylate in the presence of a phosphine,such as triphenylphosphine.

Compounds of formula (4) can be treated with hexamethylditin or diboronof formula (9), such as bis(pinacolato)diboron andbis(catecholato)diboron, wherein R is hydrogen, alkyl, butyloxycarbonyl,or benzyloxycarbonyl, in the presence of a palladium catalyst to providethe corresponding tin or boronic acid of formula (5), which is reactedwith a desired halide of a fused bicycloheterocycle represented by Ar²of formula (6), wherein X′ is bromide, chloride, or iodide, to providecompounds of formula (8). Alternatively, halides of a desired Ar² groupcan be treated with hexamethylditin or diboron of formula (9), such asbis(pinacolato)diboron and bis(catecholato)diboron, in the presence of apalladium catalyst to provide a corresponding tin or boronic acidreagent that is reacted with a compound of formula (4) in the presenceof a palladium catalyst to provide a compound of formula (8).

Quinuclidine ethers of formula (14), wherein Ar¹ is anitrogen-containing heteroaryl, for example pyridazine, and Ar² is asdefined for formula (I), can be prepared as shown in Scheme 2. Potassiumquinuclidinoxide (10) can be reacted with a dihaloaromatic ring, forexample, dichloropyridazine, of formula (11) to obtain a quinuclidineether of formula (12). The quinuclidine ether can be reacted with asuitable tin or boron reagent, as described in Scheme 1, to provide afused bicycloheterocycle substituted quinuclidine ether of formula (14).Alternatively, the quinuclidine ether of formula (12) can be treatedwith hexamethylditin or diboron of formula (9), such asbis(pinacolato)diboron and bis(catecholato)diboron, to activate thearomatic group to provide (13), wherein M is tin or boronic acid ester,and further treated with a halide of a desired group Ar² in the presenceof a palladium catalyst to provide compounds of formula (14).

Quinuclidine ethers of formula (8), wherein Ar¹ and Ar² are as definedfor formula (I) also can be obtained by the methods described in Scheme3. The activated tin or boronic acid reagent of formula (7) can becoupled with the diiodoaromatic ring of formula (17) in the presence ofa palladium catalyst to provide a compound of formula (18). Compounds offormula (18) can be reacted with 3-quinuclidinol and Cul with Cs₂CO₃ in1,10-phenanthroline as described in Org. Lett. 2002, 4, 973, to providea desired compound of formula (8).

Alternatively, the compound of formula (7) is treated with a compound offormula (19), wherein R^(a) is benzyl, in the presence of a palladiumcatalyst to provide a compound of formula (20). Compounds of formula(20), wherein R^(a) is benzyl, are hydrogenated to provide compounds offormula (21) under standard hydrogenation conditions, for example Pd/C,and further treated with 3-quinuclidinol in the presence of a phosphine,for example triphenylphosphine, and diethyl azodicarboxylate to providecompounds of formula (8).

Compounds of formula (31), wherein X is —NH— and Ar¹ and Ar² are asdescribed for compounds of formula (I), can be prepared as shown inScheme 4. 3-Quinuclidinone (25) and a haloarylamine of formula (26),wherein X′ is bromide, chloride, or iodide, can be treated with sodiumtriacetoxy borohydride and acetic acid in Na₂SO₄ to provide a compoundof formula (29). Alternatively, a compound of formula (29) can beobtained by treating 3-aminoquinuclidine (27) with haloaromatic group asdescribed in formula (28) with Cs₂CO₃ in the presence of palladiumcatalyst, preferably in toluene. A compound of formula (29) can betreated with a tin or diboron of formula (9), such asbis(pinacolato)diboron and bis(catecholato)diboron, under conditionspreviously described to provide the corresponding tin or boronic acidreagent of formula (30), which can be reacted with the halide of adesired group represented by Ar² in a compound of formula (I) to providea compound of formula (31). Alternatively, the compound of formula (29)is treated with a tin or boronic acid ester of the desired Ar² group inthe presence of a palladium catalyst to provide a compound of formula(31).

Compounds of formula (39), wherein X is S and Ar¹ and Ar² are as definedin a compound of formula (I), can be prepared as shown in Scheme 5.3-Chloroquinuclidine (35) can be reacted with a haloarylthiol of formula(36), wherein X′ is bromide, chloride, or iodide, to provide a compoundof formula (37). The compound of formula (37) can be treated with a tinor boron reagent of a desired group for Ar² as described for a compoundof formula (I) to provide a compound of formula (39). Alternatively, thecompound of formula (37) can be reacted with a hexamethylditin ordiboron reagent of formula (9), such as bis(pinacolato)diboron andbis(catecholato)diboron, in the presence of a palladium catalyst toprovide a compound of formula (38), which is reacted with the halide ofa desired Ar² group in the presence of a palladium catalyst to provide acompound of formula (39).

Compounds of formula (42), wherein X is O, R³ is NHR^(b), and Ar¹, Ar²are defined as in compounds of formula (I), can be prepared as shown inScheme 6. Compounds of formula (4) obtained as shown in Scheme 1 can betreated with a metal of the desired amino-substituted Ar² group, asdescribed for compounds of formula (I) to provide compounds of formula(42), wherein R^(b) is hydrogen, alkyl, butyloxycarbonyl, orbenzyloxycarbonyl. Compounds of formula (4) can be treated with ahexamethylditin or diboron reagent of formula (9), such asbis(pinacolato)diboron and bis(catecholato)diboron, in the presence of apalladium catalyst to provide the corresponding tin or boronic acid offormula (5), which is reacted with a desired halide of anamine-substituted fused bicycloheterocycle represented by Ar² of formula(41), wherein X′ is bromide, chloride, or iodide, to provide compoundsof formula (42).

Compounds of formula (47), wherein X is O, Ar¹ is a nitrogen containingaromatic group, for example pyridazine, R³ is NHR^(b), as previouslydefined, and Ar² is defined as in compounds of formula (I), can beprepared as shown in Scheme 7. Compounds of formula (12), which can beobtained as shown in Scheme 2, are treated with a metal of the desiredamino-substituted Ar² group, as described for compounds of formula (I),of formula (45) to provide compounds of formula (47). Compounds offormula (12) also can be treated with a hexamethylditin or diboronreagent of formula (9), such as bis(pinacolato)diboron andbis(catecholato)diboron, in the presence of a palladium catalyst toprovide the corresponding tin or boronic acid of formula (13), which isreacted with a desired halide of an amine-substituted fusedbicycloheterocycle represented by Ar² of formula (46), wherein X′ isbromide, chloride, or iodide, to provide compounds of formula (47).

Quinuclidine ethers of formula (56) and (57), wherein Ar¹ is as definedfor formula (I) and Ar² is substituted with a group NR⁵R⁶ can beobtained by the methods described in Scheme 8. Compounds of formula (50)can be treated with 3-quinuclidinol in the presence of a phosphine, forexample triphenylphosphine, and diethyl azodicarboxylate to providecompounds of formula (52). Alternatively, compounds of formula (51),wherein X″ is bromide, chloride, or iodide, can be reacted with Cul,Cs₂CO₃ in 1,10-phenanthroline as described in Org. Lett. 2002, 4, 973,to provide a desired compound of formula (52). Compounds of formula(52), wherein X″ is NO₂, can be reduced with hydrogen in the presence ofa palladium catalyst and reacted with a chloride or bromide of a desiredR group of formula (53), wherein R′ is hydrogen, alkyl, aryl,alkycarbonyl, alkoxycarbonyl, arylcarbonyl, or aryloxycarbonyl, toprovide compounds of formula (56). Compounds of formula (52), wherein X″is bromide, chloride, or iodide, can be treated with a compound R′NHR″of formula (54), wherein R′ and R″ are as previously described for R′ incompounds of formula (53), to provide a corresponding compound offormula (57).

Compounds of formulas (63), and (64) can be prepared as shown in Scheme9. 3-Quinuclidinone and a halobiarylamine of formula (60), wherein X′ isbromide, chloride, or iodide, can be treated with sodium triacetateborohydride and Na₂SO₄in 15 acetic acid to provide a compound of formula(61) as described in Tetrahedron Lett. 1996, 37, 6045. Compounds offormula (61), wherein X′ is bromide, chloride, or iodide, can be treatedwith a compound R′NHR″ of formula (54), wherein R′ and R″ are aspreviously described for R′ in compounds of formula (53), to provide acorresponding compound of formula (64). Compounds of formula (61),wherein X is NO₂, can be reduced with hydrogen in the presence of apalladium catalyst and reacted with a chloride or bromide of a desiredR′ group of formula (53), wherein R′ is hydrogen, alkyl, aryl,alkycarbonyl, alkoxycarbonyl, arylcarbonyl, or aryloxycarbonyl, toprovide compounds of formula (63).

Compounds of formula (69), wherein X is —NH—, R³ is NHR^(b), and Ar¹,Ar² are defined as in compounds of formula (I), can be prepared as shownin Scheme 10. Compounds of formula (29) obtained as shown in Scheme 7can be treated with a metal of the desired amino-substituted Ar² group,as described for compounds of formula (I), of formula (45) to providecompounds of formula (69). Compounds of formula (29) also can be treatedwith a hexamethylditin or diboron reagent of formula (9), such asbis(pinacolato)diboron and bis(catecholato)diboron, in the presence of apalladium catalyst to provide the corresponding tin or boronic acid offormula (30), which is reacted with a desired halide of anamine-substituted fused bicycloheterocycle represented by Ar² of formula(46), wherein X′ is bromide, chloride, or iodide, to provide compoundsof formula (69).

Quinuclidine biarylsulfides of formula (72) and (73), wherein Ar¹ is asdefined for formula (I) and Ar² is substituted with a group NR′R″ can beobtained by the methods described in Scheme 11. 3-Chloroquinuclidine canbe reacted with a halobiarylthiol of formula (70), wherein X″ isbromide, chloride, iodide, NO₂, or NHR′R″, as described in TetrahedronLett. 1996, 37, 6045, to provide a compound of formula (71). Compoundsof formula (71), wherein X″ is NO₂, can be reduced with hydrogen in thepresence of a palladium catalyst and reacted with a chloride or bromideof a desired R′ group of formula (53), wherein R′ is hydrogen, alkyl,aryl, alkycarbonyl, alkoxycarbonyl, arylcarbonyl, or aryloxycarbonyl, toprovide compounds of formula (72). Compounds of formula (71), wherein X″is bromide, chloride, or iodide, can be treated with a compound R′NHR″of formula (54), wherein R′ and R″ are as previously described for R′ incompounds of formula (53), to provide a corresponding compound offormula (73).

Compounds of formula (77), wherein X is S, R³ is NHR^(b), and Ar¹, Ar²are defined as in compounds of formula (I) can be prepared as shown inScheme 12. Compounds of formula (37) obtained as shown in Scheme 5 canbe treated with a metal of the desired amino-substituted Ar² group, asdescribed for compounds of formula (I), of formula (75) to providecompounds of formula (77). Compounds of formula (37) also can be treatedwith a hexamethylditin or diboron reagent of formula (9), such asbis(pinacolato)diboron and bis(catecholato)diboron, in the presence of apalladium catalyst to provide the corresponding tin or boronic acid offormula (38), which is reacted with a desired halide of anamine-substituted fused bicycloheterocycle represented by Ar² of formula(76), wherein X′ is bromide, chloride, or iodide, to provide compoundsof formula (77).

Aminobenzothiazole-substituted quinuclidines of formula (82) can beobtained as shown in Scheme 13. Amino-substituted quinuclidine ethers,thioethers, and amines of formula (80) are obtained by methods describedin Schemes 6-12. Compounds of formula (80) are reacted with bromine andKSCN in acetic acid to provide aminobenzothiazole-substitutedquinuclidines of formula (81). Compounds of formula (81) can be furthertreated with the halide of a desired R^(c) group, wherein R^(c) asdefined for R⁵ or R⁶ in compounds of formula (I) to provide the desiredaminobenzothiazole-substituted quinuclidine derivative.

The compounds and intermediates of the invention may be isolated andpurified by methods well-known to those skilled in the art of organicsynthesis. Examples of conventional methods for isolating and purifyingcompounds can include, but are not limited to, chromatography on solidsupports such as silica gel, alumina, or silica derivatized withalkylsilane groups, by recrystallization at high or low temperature withan optional pretreatment with activated carbon, thin-layerchromatography, distillation at various pressures, sublimation undervacuum, and trituration, as described for instance in “Vogel's Textbookof Practical Organic Chemistry”, 5th edition (1989), by Furniss,Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical,Essex CM20 2JE, England.

The compounds of the invention have at least one basic nitrogen wherebythe compound can be treated with an acid to form a desired salt. Forexample, a compound may be reacted with an acid at or above roomtemperature to provide the desired salt, which is deposited, andcollected by filtration after cooling. Examples of acids suitable forthe reaction include, but are not limited to tartaric acid, lactic acid,succinic acid, as well as mandelic, atrolactic, methanesulfonic,ethanesulfonic, toluenesulfonic, naphthalenesulfonic, carbonic, fumaric,gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic,phosphoric, sulfuric, citric, or hydroxybutyric acid, camphorsulfonic,malic, phenylacetic, aspartic, glutamic, and the like.

Compositions of the Invention

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically acceptable carrier. The compositionscomprise compounds of the invention formulated together with one or morenon-toxic pharmaceutically acceptable carriers. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral injection or for rectal administration.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administration,including intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms can be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It also can bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form can be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug can depend upon its rateof dissolution, which, in turn, may depend upon crystal size andcrystalline form. Alternatively, a parenterally administered drug formcan be administered by dissolving or suspending the drug in an oilvehicle.

Suspensions, in addition to the active compounds, can contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation also can be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well-known in the pharmaceutical formulatingart. They can optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials useful for delaying release of the activeagent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. A desired compound ofthe invention is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, eardrops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention also can be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants. Ophthalmicformulations, eye ointments, powders and solutions are also contemplatedas being within the scope of this invention. Aqueous liquid compositionsof the invention also are particularly useful.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts, esters, or amides derived frominorganic or organic acids. The term “pharmaceutically acceptable salts,esters and amides,” as used herein, include salts, zwitterions, estersand amides of compounds of formula (I) which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, are commensurate with a reasonable benefit/riskratio, and are effective for their intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid.

Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate; 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids which can be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid, andcitric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium, and aluminum salts, and the like,and nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine and the such as.Other representative organic amines useful for the formation of baseaddition salts include ethylenediamine, ethanolamine, diethanolamine,piperidine, and piperazine.

The term “pharmaceutically acceptable ester,” as used herein, refers toesters of compounds of the invention which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Examples of pharmaceutically acceptable,non-toxic esters of the invention include C₁-to-C₆ alkyl esters andC₅-to-C₇ cycloalkyl esters, although C₁-to-C₄ alkyl esters arepreferred. Esters of the compounds of formula (I) can be preparedaccording to conventional methods. Pharmaceutically acceptable esterscan be appended onto hydroxy groups by reaction of the compound thatcontains the hydroxy group with acid and an alkylcarboxylic acid such asacetic acid, or with acid and an arylcarboxylic acid such as benzoicacid. In the case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine and an alkyl halide, alkyl trifilate, forexample with methyl iodide, benzyl iodide, cyclopentyl iodide. They alsocan be prepared by reaction of the compound with an acid such ashydrochloric acid and an alkylcarboxylic acid such as acetic acid, orwith acid and an arylcarboxylic acid such as benzoic acid.

The term “pharmaceutically acceptable amide,” as used herein, refers tonon-toxic amides of the invention derived from ammonia, primary C₁-to-C₆alkyl amines and secondary C₁-to-C₆ dialkyl amines. In the case ofsecondary amines, the amine can also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₁-to-C₃ alkyl primary amides and C₁-to-C₂ dialkyl secondaryamides are preferred. Amides of the compounds of formula (I) can beprepared according to conventional methods. Pharmaceutically acceptableamides can be prepared from compounds containing primary or secondaryamine groups by reaction of the compound that contains the amino groupwith an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide.In the case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. They also can beprepared by reaction of the compound with an acid such as sulfuric acidand an alkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid under dehydrating conditions aswith molecular sieves added. The composition can contain a compound ofthe invention in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the invention can be rapidly transformed in vivo to a parentcompound of formula (I), for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987).

The invention contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in vivo biotransformation tocompounds of formula (I).

Methods of the Invention

Compounds and compositions of the invention are useful for modulatingthe effects of nAChRs, and more particularly α7 nAChRs. In particular,the compounds and compositions of the invention can be used for treatingand preventing disorders modulated by α7 nAChRs. Typically, suchdisorders can be ameliorated by selectively modulating the α7 nAChRs ina mammal, preferably by administering a compound or composition of theinvention, either alone or in combination with another active agent, forexample, as part of a therapeutic regimen.

The compounds of the invention, including but not limited to thosespecified in the examples, possess an affinity for nAChRs, and moreparticularly α7 nAChRs. As α7 nAChRs ligands, the compounds of theinvention can be useful for the treatment and prevention of a number ofα7 nAChR-mediated diseases or conditions.

For example, α7 nAChRs have been shown to play a significant role inenhancing cognitive function, including aspects of learning, memory andattention (Levin, E. D., J. Neurobiol. 53: 633-640, 2002). As such, α7ligands are suitable for the treatment of cognitive disorders including,for example, attention deficit disorder, attention deficit hyperactivitydisorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment,senile dementia, AIDS dementia, Pick's Disease, dementia associated withLewy bodies, and dementia associated with Down's syndrome, as well ascognitive deficits associated with schizophrenia.

In addition, α7-containing nAChRs have been shown to be involved in theneuroprotective effects of nicotine both in vitro (Jonnala, R. B. andBuccafusco, J. J., J. Neurosci. Res. 66: 565-572, 2001) and in vivo(Shimohama, S. et al., Brain Res. 779: 359-363, 1998). Moreparticularly, neurodegeneration underlies several progressive CNSdisorders, including, but not limited to, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, Huntington'sdisease, dementia with Lewy bodies, as well as diminished CNS functionresulting from traumatic brain injury. For example, the impairedfunction of α7 nAChRs by β-amyloid peptides linked to Alzheimer'sdisease has been implicated as a key factor in development of thecognitive deficits associated with the disease (Liu, Q.-S., Kawai, H.,Berg, D. K., PNAS 98: 4734-4739, 2001). The activation of α7 nAChRs hasbeen shown to block this neurotoxicity (Kihara, T. et al., J. Biol.Chem. 276: 13541-13546, 2001). As such, selective ligands that enhanceα7 activity can counter the deficits of Alzheimer's and otherneurodegenerative diseases.

Schizophrenia is a complex disease that is characterized byabnormalities in perception, cognition, and emotions. Significantevidence implicates the involvement of α7 nAChRs in this disease,including a measured deficit of these receptors in post-mortem patients(Leonard, S. Eur. J. Pharmacol. 393: 237-242, 2000). Deficits in sensoryprocessing (gating) are one of the hallmarks of schizophrenia. Thesedeficits can be normalized by nicotinic ligands that operate at the α7nAChR (Adler L. E. et al., Schizophrenia Bull. 24: 189-202,1998;Stevens, K. E. et al., Psychopharmacology 136: 320-327, 1998). Thus, α7ligands demonstrate potential in the treatment schizophrenia.

Angiogenesis, a process involved in the growth of new blood vessels, isimportant in beneficial systemic functions, such as wound healing,vascularization of skin grafts, and enhancement of circulation, forexample, increased circulation around a vascular occlusion.Non-selective nAChR agonists like nicotine have been shown to stimulateangiogenesis (Heeschen, C. et al., Nature Medicine 7: 833-839, 2001).Improved angiogenesis has been shown to involve activation of the α7nAChR (Heeschen, C. et al, J. Clin. Invest. 110: 527-536, 2002).Therefore, nAChR ligands that are selective for the α7 subtype offerimproved potential for stimulating angiogenesis with an improved sideeffect profile.

A population of α7 nAChRs in the spinal cord modulate serotonergictransmission that have been associated with the pain-relieving effectsof nicotinic compounds (Cordero-Erausquin, M. and Changeux, J.-P. PNAS98:2803-2807, 2001). The α7 nAChR ligands demonstrate therapeuticpotential for the treatment of pain states, including acute pain,post-surgical pain, as well as chronic pain states includinginflammatory pain and neuropathic pain. Moreover, α7 nAChRs areexpressed on the surface of primary macrophages that are involved in theinflammation response, and that activation of the α7 receptor inhibitsrelease of TNF and other cytokines that trigger the inflammationresponse (Wang, H. et al Nature 421: 384-388, 2003). Therefore,selective α7 ligands demonstrate potential for treating conditionsinvolving inflammation and pain.

The mammalian sperm acrosome reaction is an exocytosis process importantin fertilization of the ovum by sperm. Activation of an α7 nAChR on thesperm cell has been shown to be essential for the acrosome reaction(Son, J.-H. and Meizel, S. Biol. Reproduct. 68: 1348-1353 2003).Consequently, selective α7 agents demonstrate utility for treatingfertility disorders.

Compounds of the invention are particularly useful for treating andpreventing a condition or disorder affecting cognition,neurodegeneration, and schizophrenia.

Cognitive impairment associated with schizophrenia often limits theability of patients to function normally, a symptom not adequatelytreated by commonly available treatments, for example, treatment with anatypical antipsychotic. (Rowley, M. et al., J. Med. Chem. 44: 477-501,2001). Such cognitive deficit has been linked to dysfunction of thenicotinic cholinergic system, in particular with decreased activity atα7 receptors. (Friedman, J. I. et al., Biol Psychiatry, 51: 349-357,2002). Thus, activators of α7 receptors can provide useful treatment forenhancing cognitive function in schizophrenic patients who are beingtreated with atypical antipsychotics. Accordingly, the combination of anα7 nAChR ligand and an atypical antipsychotic would offer improvedtherapeutic utility. Specific examples of suitable atypicalantipsychotics include, but are not limited to, clozapine, risperidone,olanzapine, quietapine, ziprasidone, zotepine, iloperidone, and thelike.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the invention can be employed in pureform or, where such forms exist, in pharmaceutically acceptable salt,ester, amide or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptablecarriers. The phrase “therapeutically effective amount” of the compoundof the invention means a sufficient amount of the compound to treatdisorders, at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be understood, however, that the total daily usage ofthe compounds and compositions of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal range from about 0.10 mg/kg body weight to about1 g/kg body weight. More preferable doses can be in the range of fromabout 0.10 mg/kg body weight to about 100 mg/kg body weight. If desired,the effective daily dose can be divided into multiple doses for purposesof administration. Consequently, single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose.

The compounds and processes of the invention will be better understoodby reference to the following examples and reference examples, which areintended as an illustration of and not a limitation upon the scope ofthe invention.

EXAMPLES Example 13-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole Example 1A3-(4-iodophenoxy)quinuclidine

Under N₂, the mixture of 3-hydroxy quinuclidine (Aldrich, 2.54 g, 20mmol), 1,4-diiodobenzene (Aldrich, 7.9 g, 24 mmol), Cul (StremChemicals, 0.38 g, 2 mmol) and 1,10-phenanthroline (Aldrich, 0.72 g, 4mmol) in toluene (anhydrous, Aldrich, 50 mL) was stirred at 110° C. for40 h. After the reaction went to completion, the reaction mixture wasdiluted with chloroform (100 mL) and washed with water (2×10 mL). Theorganic solution was concentrated and the title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.20) as oil(3.7 g, yield, 56%). ¹H NMR (300 MHz, CD₃OD) δ 1.40-1.56 (m, 1H),1.64-1.80 (m, 2H), 1.90-2.08 (m,1H), 2.10-2.21 (m,1H), 2.60-3.00 (m,5H), 3.34-3.40 (m, 1H), 4.46 (m, 1H), 6.73 (d, J=8.8 Hz, 2H), 7.56 (d,J=8.8, Hz, 2H), ppm. MS (DCI/NH₃) m/z 330 (M+H)⁺.

Example 1B 3-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole

The mixture of the product of Example 1A (330 mg, 1 mmol),N-(2-ethynyl-phenyl)-2,2,2-trifluoro-acetamide (ref. Tetrahedron Lett.1992, 33, 3915.; 280 mg, 1.3 mmol), Pd₂(dba)₃ (Aldrich, 19 mg, 0.02mmol) and K₂CO₃ (180 mg, 1.3 mmol) in DMSO (3 mL) was stirred at 40° C.under N₂ for 2 hours. The reaction was monitored with TLC. After thereaction was complete, it was cooled down to room temperature anddiluted with EtOAc (50 mL). It was then washed with brine (3×5 mL). Theorganic solution was concentrated and the title product was purified bypreparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. ElutingSolvent, MeCN/H₂O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.)Flow rate, 75 mL/min., uv, 250 nm) as solid (113 mg, yield, 36%). ¹H NMR(300 MHz, CD₃OD) δ 1.43-1.57 (m, 1H), 1.62-1.89 (m, 2H), 2.01-2.15 (m,1H), 2.16-2.23 (m, 1H), 2.73-3.03 (m, 5H), 3.28-3.40 (m, 1H), 4.51-4.58(m, 1H), 6.97 (dt, J=8.8, 2.1 Hz, 2H), 7.03-7.17 (m, 2H), 7.36 (s, 1H),7.37-7.42 (m, 1H), 7.57 (dt, J=8.8, 2.0 Hz, 2H), 7.81 (dt, J=7.8, 1.2Hz, 1H) ppm. MS (DCI/NH₃) m/z 319 (M+H)⁺.

Example 1C 3-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indolehemifumarate

The product of Example 1B (113 mg, 0.36 mmol) was treated with fumaricacid (46 mg, 0.4 mmol) in EtOAc/EtOH (v.1:1, 4 mL) at ambienttemperature for 10 h. The title compound was obtained as solid (131 mg,yield, 89%). ¹H NMR (300 MHz, CD₃OD) δ 1.73-2.13 (m, 3H), 2.23-2.37 (m,1H), 2.43-2.51 (m, 1H), 3.12-3.43 (m, 5H), 3.64-3.76 (m, 1H), 4.77-4.88(m, 1H), 6.67 (s, 1.4H), 6.99-7.18 (m, 4H), 7.38 (s, 1H), 7.39-7.43 (m,1H), 7.61 (dt, J=8.8, 2.0 Hz, 2H), 7.80 (d, J=7.8 Hz, 1H) ppm. MS(DCI/NH₃): m/z 319 (M+H)⁺. Anal. Calculated for C₂₁H₂₂N₂O.0.85 C₄H₄O₄:C,70.27; H, 6.14; N, 6.72. Found: C, 70.20; H, 6.35; N, 6.88.

Example 2 4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]- 1H-indoleExample 2A 3-[4-(trimethylstannyl)phenoxy]quinuclidine

The mixture of the product from Example 1A (330 mg, 1 mmol),hexamethylditin (Aldrich, 654 mg, 2 mmol) and Pd(PPh₃)₄ (Aldrich, 116mg, 0.1 mmol) in toluene (10 mL) was stirred at 110° C. under N₂ for 2hours. The reaction was monitored with TLC. After the reaction wascomplete, it was cooled down to room temperature and diluted with EtOAc(50 mL). It was then washed with brine (2×5 mL). The organic solutionwas concentrated under reduced pressure and the title compound waspurified by flash chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1,R_(f). 0.35) as solid (300 mg, yield, 82%). ¹H NMR (300 MHz, CD₃OD) δ0.25 (s, 9H), 1.79-2.16 (m, 3H), 2.23-2.36 (m, 1H), 2.45-2.52 (m, 1H),3.17-3.43 (m, 5H), 3.73-3.83 (m, 1H), 4.84-4.92 (m, 1H), 6.96 (d, J=8.5Hz, 2H), 7.41 (d, J=8.5 Hz, 2H) ppm. MS (DCI/NH₃): m/z 364 (M+H)⁺, 366(M+H)⁺, 368 (M+H)⁺.

Example 2B 4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole

The product of 2A (300 mg, 0.8 mmol), 4-bromoindole (Aldrich, 196 mg, 1mmol), Pd₂(dba)₃ (Aldrich, 27 mg, 0.03 mmol) and (o-tol.)₃P (Aldrich, 27mg, 0.09 mmol) in DMF (Aldrich, anhydrous, 5 mL) were heated to 80° C.under N₂ and stirred overnight. It was then cooled down to roomtemperature and diluted with EtOAc (50 mL). The mixture was washed withbrine (2×5 mL). The organic solution was concentrated under reducedpressure and the title compound was purified by flash chromatography(SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.30) as a solid (48 mg,yield, 19%). ¹H NMR (300 MHz, CD₃OD) δ 1.46-1.58 (m, 1H), 1.64-1.91 (m,2H), 2.01-2.17 (m, 1H), 2.19-2.26 (m, 1H), 2.75-3.03 (m, 5H), 3.32-3.42(m, 1H), 4.55-4.63 (m, 1H), 6.58 (dd, J=3.4, 1.0 Hz, 1H), 6.98-7.04 (m,3H), 7.14 (t, J=7.8 Hz, 1H), 7.25 (d, J=3.1 Hz, 1H), 7.33 (dt, J=8.1,1.0 Hz, 1H), 7.59 (dt, J=9.2, 2.7 Hz, 2H) ppm. MS (DCI/NH₃): m/z 319(M+H)⁺.

Example 2C 4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indolefumarate

The product of Example 2B (48 mg, 0.15 mmol) was treated with fumaricacid (23 mg, 0.2 mmol) in EtOAc/EtOH (v. 1:1, 3 mL) at ambienttemperature for 15 h. The title compound was obtained as solid (60.2 mg,yield, 90%). ¹H NMR (300 MHz, CD₃OD) δ 1.82-2.19 (m, 3H), 2.29-2.42 (m,1H), 2.51-2.58 (m, 1H), 3.16-3.46 (m, 5H), 3.75-3.85 (m, 1H), 4.89-4.96(m, 1H), 6.56 (dd, J=3.4, 1.0 Hz, 1H), 6.69 (s, 2.2H), 7.02 (dd, J=7.1,1.0 Hz, 1H), 7.08 (dt, J=8.8, 2.5 Hz, 2H), 7.15 (t, J=7.5 Hz, 1H), 7.26(d, J=3.4 Hz, 1H), 7.35 (dt, J=8.1, 1.0 Hz, 1H), 7.64 (dt, J=8.8, 2.6Hz, 2H) ppm. MS (DCI/NH₃): m/z 319 (M+H)⁺. Anal. Calculated forC₂₁H₂₂N₂O.1.12 C₄H₄O₄:C, 68.25; H, 5.95; N, 6.25. Found: C, 68.43; H,5.58; N, 6.20.

Example 3 5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole Example3A 5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole

Under N₂, the product of Example 1A (329 mg, 1 mmol), 5-indolylboronicacid (Frontier, 193 mg, 1.2 mmol), Pd₂(dba)₃ (Aldrich, 24 mg, 0.025mmol), (^(t)Bu₃P)₂ Pd (26 mg, 0.05 mmol), K₂CO₃ (276 mg, 2 mmol) and KF(80 mg, 1.4 mmol) in THF(8 mL) was stirred at 60° C. overnight. Thereaction was monitored with TLC. After the reaction was complete, it wasdiluted with EtOAc (30 mL) and washed with brine (2×5 mL). The organicsolution was concentrated under reduced pressure and the title productwas purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm,40×100 mm. Eluting Solvent, MeCN/H₂O (with 0.2% v. TFA) (v. 90/10 to10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (80 mg,yield, 25%). ¹H NMR (300 MHz, CD₃OD) δ 1.44-1.58 (m, 1H), 1.62-1.90 (m,2H), 2.01-2.15 (m, 1H), 2.16-2.24 (m, 1H), 2.74-3.04 (m, 5H), 3.27-3.40(m, 1H), 4.51-4.59 (m, 1H), 6.46 (dd, J=3.4, 1.1 Hz, 1H), 6.95 (dt,J=8.8, 2.6 Hz, 2H), 7.22 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz,1H), 7.40 (dt, J=8.5, 1.0 Hz, 1H), 7.54 (dt, J=9.2, 2.6 Hz, 2H), 7.71(dd, J=1.7, 0.7 Hz, 1H) ppm. MS (DCI/NH₃): m/z 319 (M+H)⁺.

Example 3B 5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indolefumarate

The product of Example 3A (80 mg, 0.25 mmol) was treated with fumaricacid (29 mg, 0.25 mmol) in EtOAc/EtOH (v.1:1, 4 mL) at ambienttemperature for 10 h. The title compound was obtained as solid (57 mg,yield, 52%). ¹H NMR (300 MHz, CD₃OD) δ 1.78-2.16 (m, 3H), 2.25-2.39 (m,1H), 2.46-2.54 (m, 1H), 3.14-3.45 (m, 5H), 3.69-3.81 (m, 1H), 4.80-4.89(m, 1H), 6.46 (dd, J=3.0, 1.0, 1H), 6.68 (s, 2H), 7.02 (dt, J=8.8, 2.5Hz, 2H), 7.23 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.43 (dt,J=8.4, 0.8 Hz, 1H), 7.58 (dt, J=9.2, 2.6 Hz, 2H), 7.71 (dd, J=1.7, 1.0Hz, 1H) ppm. MS (DCI/NH₃): m/z 319 (M+H)⁺. Anal. Calculated forC₂₁H₂₂N₂O.C₄H₄O₄:C, 69.11; H, 6.03; N, 6.45. Found: C, 69.23; H, 5.81;N, 6.59.

Example 4 5-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-1H-indoleExample 4A (3R)-3-Quinuclidinol

(3R)-3-Quinuclidinol hydrochloride (Aldrich, 20 g, 12.2 mmol) wastreated with NaOH aqueous solution(20%, 50 mL) at ambient temperaturefor 10 min. It was then extracted with CHCl₃/^(i)PrOH (v.10: 1, 3×200mL). The extracts were combine, washed with brine (50 mL) and dried overMgSO₄. The drying agents were removed by filtration and the filtrateswas concentrated under reduced pressure to give the title compound aswhite solid (15. 5 g, yield, 99%). ¹H NMR (300 MHz, CD₃OD) δ 1.36-1.50(m, 1H), 1.52-1.60 (m, 1H), 1.76-1.85 (m, 2H), 1.90-2.05 (m, 1H),2.50-2.95(m, 5H), 3.10 (ddd, J=14.2, 8.4, 2.3 Hz, 1H), 3.82-3.88 (m, 1H)ppm. MS (DCI/NH₃): m/z 128 (M+H)⁺.

Example 4B (3R)-3-(4-bromophenoxy)quinuclidine

The product of Example 4A (1.27 g, 10 mmol) was coupled with1-iodo-4-bromobenzene (Aldrich, 2.83 g, 10 mol) according to theprocedure of Example 1A. The title product was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.30) assolid (400 mg, yield, 14%). ¹H NMR (300 MHz, CD₃OD) δ 1.41-1.54 (m, 1H),1.59-1.73 (m, 1H), 1.73-1.86 (m, 1H), 1.92-2.06 (m, 1H), 2.09-2.17 (m,1H), 2.71-2.97 (m, 5H), 3.24-3.34 (m, 1H), 4.45-4.52 (m, 1H), 6.83 (dt,J=9.2, 2.6 Hz, 2H), 7.37 (dt, J=9.2, 2.7 Hz, 2H) ppm. MS (DCI/NH₃): m/z282 (M+H)⁺, 284 (M+H)⁺.

Example 4C 5-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-1H-indole

The product of 4C (282 mg, 1 mmol) coupled with 5-indolylboronic acid(Frontier, 190 mg, 1.2 mmol) according to the procedure of Example 3A.The title product was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.35) as solid (50 mg, yield, 16%).¹H NMR (300 MHz, CD₃OD) δ 1.44-1.58 (m, 1H), 1.62-1.90 (m, 2H),2.01-2.15 (m, 1H), 2.16-2.24 (m, 1H), 2.74-3.04 (m, 5H), 3.27-3.40 (m,1H), 4.51-4.59 (m, 1H), 6.46 (dd, J=3.4, 1.1 Hz, 1H), 6.95 (dt, J=8.8,2.6 Hz, 2H), 7.22 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.40(dt, J=8.5, 1.0 Hz, 1H), 7.54 (dt, J=9.2, 2.6 Hz, 2H), 7.71 (dd, J=1.7,0.7 Hz, 1H) ppm. MS (DCI/NH₃): m/z 319 (M+H)⁺.

Example 4D 5-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-1H-indolefumarate

The product of Example 4C (50 mg, 0.25 mmol) was treated with fumaricacid (29 mg, 0.25 mmol) in EtOAc/EtOH (v. 1:1, 4 mL) at ambienttemperature for 10 h. The title compound was obtained as solid (56.9 mg,yield, 52%). ¹H NMR (300 MHz, CD₃OD) δ 1.78-2.16 (m, 3H), 2.25-2.39 (m,1H), 2.46-2.54 (m, 1H), 3.14-3.45 (m, 5H), 3.69-3.81 (m, 1H), 4.80-4.89(m, 1H), 6.46 (dd, J=3.0, 1.0, 1H), 6.68 (s, 2.2H), 7.02 (dt, J=8.8, 2.5Hz, 2H), 7.23 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.43 (dt,J=8.4, 0.8 Hz, 1H), 7.58 (dt, J=9.2, 2.6 Hz, 2H), 7.71 (dd, J=1.7, 1.0Hz, 1H) ppm. MS (DCI/NH₃): m/z 319 (M+H)⁺. Anal. Calculated forC₂₁H₂₂N₂O.1.14 C₄H₄O₄:C, 68.11; H, 5.94; N, 6.21. Found: C, 68.12; H,6.04; N, 6.18.

Example 5 6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]- 1H-indoleExample 5A 6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole

The product of Example 2A (300 mg, 0.8 mmol) was coupled with6-bromoindole (Aldrich, 196 mg, 1 mmol) according to the procedure in2B. The title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.20) as a solid (30 mg, yield,12%). ¹H NMR (300 MHz, CD₃OD) δ 1.45-1.58 (m, 1H), 1.64-1.90 (m, 2H),2.01-2.15 (m, 1H), 2.17-2.24 (m, 1H), 2.75-3.04 (m, 5H), 3.30-3.42 (m,1H), 4.53-4.61 (m, 1H), 6.43 (dd, J=3.1, 0.7 Hz, 1H), 6.97 (dt, J=8.8,2.6 Hz, 2H), 7.21-7.27 (m, 2H), 7.52-7.60 (m, 4H) ppm. MS (DCI/NH₃): m/z319 (M+H)⁺.

Example 5B 6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]- 1H-indolefumarate

The product of Example 5A (30 mg, 0.1 mmol) was treated with fumaricacid (12 mg, 0.1 mmol) in EtOAc/EtOH (v. 1:1, 2 mL) at ambienttemperature for 15 h. The title compound was obtained as solid (38.4 mg,yield, 79%). ¹H NMR (300 MHz, CD₃OD) δ 1.80-2.19 (m, 3H), 2.27-2.40 (m,1H), 2.48-2.56 (m, 1H), 3.17-3.63 (m, 5H), 3.72-3.83 (m, 1H), 4.80-4.88(m, 1H), 6.43 (dd, J=3.1, 0.7 Hz, 1H), 6.68 (s, 2H), 7.04 (dt, J=8.8,2.5 Hz, 2H), 7.21-7.27 (m, 2H), 7.53-7.65 (m, 4H) ppm. MS(DCI/NH₃): m/z319 (M+H)⁺. Anal. Calcd. for C₁₉H₂₀N₄O.1.3 C₄H₄O₄:C, 67.05; H, 5.84; N,5.97. Found: C, 67.15; H, 5.99; N, 5.95.

Example 6 2-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole Example6A 3-(4-ethynylphenoxy)quinuclidine

Under N₂, the mixture of the product from Example 1A (800 mg, 2.4 mmol),trimethylsilylacetylene (Aldrich, 392 mg, 4 mmol), Pd(PPh₃)₄ (Aldrich,29 mg, 0.025 mmol) and Cul (Strem Chemicals, 10 mg, 0.05 mmol) in DMF(10 mL) was stirred at ambient temperature overnight. DMF then wasremoved under reduced pressure. The residue was treated with tetrabutylammonium fluoride (Aldrich, in THF, 1 M, 5 mL) at room temperature for 3h. The reaction was monitored with TLC. After the reaction was complete,it was diluted with EtOAc (50 mL) and washed with brine (2×10 mL). Theorganic solution was concentrated and the title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃ H₂O, 90:10:1, R_(f). 0.30) as asolid (560 mg, yield, 99%). ¹H NMR (300 MHz, CD₃OD) δ 1.42-1.54 (m, 1H),1.61-1.87 (m, 2H), 1.93-2.07 (m, 1H), 2.10-2.18 (m, 1H), 2.71-3.00 (m,5H), 3.19-3.37 (m, 2H), 4.49-4.56 (m,1H), 6.86 (d, J=8.8 Hz, 2H), 7.37(d, J=8.8 Hz, 2H) ppm. MS (DCI/NH₃): m/z 228 (M+H)⁺.

Example 6B 2,2,2-trifluoro-N-(2-iodophenyl)acetamide

2-Iodo-phenylamine (Aldrich, 1.09 g, 5 mmol) was treated withtrifluoroacetic anhydride (Aldrich, 1.26 g, 6 mmol) and2,6-di-tert-butyl-4-methyl-pyridine (Aldrich, 1.23 g, 6 mmol) in CH₂Cl₂(10 mL)at room temperature overnight. It was then quenched with withwater (5 mL) and extracted with EtOAc (3×10 mL). The extracts werecombined and washed with brine (5 mL). The organic solution wasconcentrated and the title compound was purified by flash chromatography(SiO₂, Hexanes/EtOAc, 80:20, R_(f). 0.50) as a solid (1.1 g, yield,70%). ¹H NMR (300 MHz, CD₃OD) δ 7.07-7.12 (m, 1H), 7.39-7.47 (m, 2H),7.95 (dd, J=7.8, 1.3 Hz, 1H) ppm. MS (DCI): m/z 316 (M+H)⁺.

Example 6C 2-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole

Under N₂, the mixture of product from Example 6A (114 mg, 0.5 mmol), theproduct from Example 6B (157 mg, 0.5 mmol), Cul (Strem Chemicals, 14 mg,0.075 mmol), PPh₃ (Aldrich, 39 mg, 0.15 mmol) and K₃PO₄ (212 mg, 1 mmol)in dioxane (5 mL) was stirred at 80° C. for 20 h. After the reaction wascomplete, it was diluted with EtOAc (30 mL) and washed with brine (2×5mL). The organic solution was concentrated under reduced pressure andthe title compound was purified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃H₂O, 90:10:1, R_(f). 0.30) as solid (70 mg, yield, 44%). ¹H NMR (300MHz, CD₃OD) δ 1.45-1.59 (m,1H), 1.65-1.91 (m, 2H), 2.00-2.14 (m, 1H),2.17-2.24 (m, 1H), 2.75-3.01 (m, 5H), 3.31-3.42 (m, 1H), 4.54-4.62(m,1H), 6.66 (d, J=0.7 Hz,1H), 6.93-7.00 (m, 3H), 7.01-7.08 (m,1H), 7.35(dq, J=8.2, 1.0 Hz, 1H), 7.48 (dq, J=7.8, 0.7 Hz, 1H), 7.71 (dt, J=8.8,2.6 Hz, 2H) ppm. MS (DCI/NH₃): m/z 319 (M+H)⁺.

Example 6D 2-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indolefumarate

The product of Example 6C (70 mg, 0.22 mmol) was treated with fumaricacid (29 mg, 0.25 mmol) in EtOAc/EtOH (v.1:1, 3 mL) at ambienttemperature for 10 h. The title compound was obtained as solid (87 mg,yield, 89%). ¹H NMR (300 MHz, CD₃OD) δ 1.81-2.18(m, 3H), 2.25-2.39 (m,1H), 2.48-2.56 (m, 1H), 3.19-3.48 (m, 5H), 3.73-3.85 (m, 1H), 4.86-4.93(m, 1H), 6.65-6.80 (m, 2H), 6.94-7.10 (m, 4H), 7.36 (dd, J=8.1, 0.7 Hz,1H), 7.49 (dt, J=7.8, 1.0 Hz, 1H), 7.75 (dt, J=9.2, 2.4 Hz, 2H) ppm. MS(DCI/NH₃): m/z 319 (M+H)⁺. Anal. Calculated for C₂₁H₂₂N₂O.1.1 C₄H₄O₄:C,68.39; H, 5.96; N, 6.28. Found: C, 68.10; H, 6.22; N, 6.25.

Example 7 5-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indoleExample 7A 3-[(6-chloropyridazin-3-yl)oxy]quinuclidine

3-Quinuclidinol (Aldrich, 508 mg, 4 mmol) was treated with ^(t)BuOK(Aldrich, 448 mg, 4 mmol) in THF(20 mL) at ambient temperature for 1hour. 3,6-Dichloropyradazine (Aldrich, 740 mg, 5 mmol) was then added.The mixture was stirred at ambient temperature for additional 1 h. Thereaction was monitored with TLC. After the reaction was complete, it wasconcentrated under reduced pressure. The residue was dissolved inCHCl₃/^(i)PrOH (v.10:1, 50 mL) and washed with brine (2×5 mL). Theorganic solution was concentrated under reduced pressure and the titlecompound was purified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O,90:10:1, R_(f). 0.45) as a solid (780 mg, yield, 82%). ¹H NMR (300 MHz,CD₃OD) δ 1.48-1.61 (m, 1H), 1.65-1.90 (m, 2H), 1.94-2.08 (m, 1H),2.23-2.31 (m, 1H), 2.73-3.01 (m, 5H), 3.37-3.48 (m, 1H), 5.18-5.27 (m,1H), 7.23 (d, J=9.2 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H) ppm. MS(DCI/NH₃):240 (M+H)⁺.

Example 7B 5-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indole

The product of Example 7A (200 mg, 0.8 mmol) was coupled with5-indolylboronic acid (161 mg, 1 mmol) according to the procedure ofExample 3A. The title product was purified by preparative HPLC (Gilson,column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H₂O (with0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv,250 nm) as solid (35 mg, yield, 14%). ¹H NMR (300 MHz, CD₃OD) 61.50-1.65(m, 1H), 1.70-1.93 (m, 2H), 2.00-2.16 (m, 1H), 2.29-2.37 (m, 1H),2.78-3.05 (m, 5H), 3.44-3.55 (m, 1H), 5.26-5.35 (m, 1H), 6.56(dd, J=3.3,1.1 Hz, 1H)), 7.25 (d, J=9.2 Hz, 1H), 7.31 (d, J=3.4 Hz, 1H), 7.51 (d,J=8.8 Hz, 1H), 7.73 (dd, J=8.5, 1.7 Hz, 1H), 8.08 (d, J=9.5 Hz, 1H),8.14 (d, J=1.7 Hz, 1H) ppm. MS (DCI/NH₃): m/z 321 (M+H)⁺.

Example 7C5-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indolehemifumarate

The product of Example 7B (35mg, 0.11 mmol) was treated with fumaricacid (23 mg, 0.2 mmol) in EtOAc/EtOH (v.1:1, 3 mL) at ambienttemperature for 10 h. The title compound was obtained as solid (42 mg,yield, 99%). ¹H NMR (300 MHz, CD₃OD) δ 1.76-1.91 (m, 1H), 1.92-2.13 (m,2H), 2.22-2.36 (m, 1H), 2.51-2.59 (m, 1H), 3.12-3.40 (m, 5H), 3.77-3.88(m, 1H), 5.42-5.51 (m, 1H), 6.56 (dd, J=2.0, 1.0Hz, 1H), 6.67 (s,1H),7.27-7.33 (m, 2H), 7.52 (dt, J=8.5, 1.0 Hz, 1H), 7.74 (dd, J=8.8, 1.7Hz,1H), 8.10-8.16 (m, 2H) ppm. MS (DCI/NH₃): m/z 321 (M+H)⁺. Anal.Calculated for C₁₉H₂₀N₄O.0.55 C₄H₄O₄:C, 66.27; H, 5.82; N, 14.58. Found:C, 66.12; H, 5.53; N, 14.63.

Example 8 4-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indoleExample 8A4-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indole

Under N₂, the mixture of Example 7A (168 mg, 0.7 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (ref.WO02055517,170 mg, 0.7 mmol), Pd₂(dba)₃ (Aldrich, 19 mg, 0.02 mmol),1,3-bis(2,6-iso-propylphenyl)imidazolium chloride (Strem Chemicals, 26mg, 0.06 mmol) and aqueous Na₂CO₃ (2 M, 1 mL) in toluene (10 mL) wasstirred at 110° C. overnight, After the reaction was complete, it wascooled down to room temperature and diluted with EtOAc (30 mL). Themixture was then washed with brine (2×5 mL) and the title compound waspurified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f).0.10) as solid (45 mg, yield, 20%). ¹H NMR (300 MHz, CD₃OD) δ 1.51-1.65(m, 1H), 1.70-1.93 (m, 2H), 2.01-2.16 (m, 1H), 2.31-2.39 (m, 1H),2.78-3.09 (m, 5H), 3.45-3.56 (m, 1H), 5.30-5.38 (m, 1H), 6.78 (dd,J=3.4, 1.0 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.30 (d, J=9.5 Hz,1H), 7.36(d, J=3.1 Hz,1H), 7.40 (dd, J=7.5, 1.0 Hz, 1H), 7.52 (dt, J=8.1, 1.0 Hz,1H), 8.07 (d, J=9.2 Hz, 1H) ppm. MS (DCI/NH₃): m/z 321 (M+H)⁺.

Example 8B4-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indole fumarate

The product of Example 8A (45 mg, 0.14 mmol) was treated with fumaricacid (23 mg, 0.2 mmol) in EtOAc/EtOH (v.1: 1, 3 mL) at ambienttemperature for 10 h. The title compound was obtained as solid (56 mg,yield, 85%). ¹H NMR (300 MHz, CD₃OD) δ 1.90-2.23 (m, 3H), 2.33-2.48 (m,1H), 2.62-2.70 (m,1H), 3.21-3.54 (m, 5H), 3.92-4.03 (m, 1H), 5.54-5.62(m, 1H), 6.69 (s, 2.5H), 6.78 (dd, J=3.4, 1.0 Hz, 1H), 7.26 (t, J=7.5Hz, 1H), 7.35-7.44 (m, 3H), 7.55 (dt, J=8.1, 1.1 Hz, 1H), 8.13 (d, J=9.2Hz, 1H) ppm. MS (DCI/NH₃): m/z 321 (M+H)⁺. Anal. Calculated forC₁₉H₂₀N₄O.1.3 C₄H₄O₄:C, 61.67; H, 5.39; N, 11.89. Found: C, 61.49; H,5.52; N, 12.17.

Example 95-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indoleExample 9A (3R)-3-[(6-chloropyridazin-3-yl)oxy]quinuclidine

The product of Example 4A (635 mg, 5 mmol) was coupled with3,6-dichloropyridazine (Aldrich, 925 mg, 6.25 mmol) according to theprocedure of Example 7A. The title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.45) assolid (750 mg, yield, 63%). ¹H NMR (300 MHz, CD₃OD) δ 1.54-1.68 (m, 1H),1.71-1.95 (m, 2H), 2.00-2.14 (m, 1H), 2.28-2.36 (m, 1H), 2.83-3.08 (m,5H), 3.44-3.56 (m, 1H), 5.23-5.30 (m, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.66(d, J=9.2 Hz, 1H) ppm. MS (DCI/NH₃): 240 (M+H)⁺.

Example 9B5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole

The product of Example 9A (480 mg, 2 mmol) was coupled with5-indolylboronic acid (Frontier, 403 mg, 2.5 mmol) according to theprocedure of Example 3A. The title product was purified by preparativeHPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent,MeCN/H₂O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate,75 mL/min., uv, 250 nm) as solid (240 mg, yield, 38%). ¹H NMR (300 MHz,CD₃OD) δ 1.49-1.64 (m, 1H), 1.68-1.93 (m, 2H), 2.00-2.15 (m, 1H),2.28-2.36 (m, 1H), 2.76-3.05 (m, 5H), 3.43-3.55 (m, 1H), 5.26-5.34 (m,1H), 6.56 (dd, J=3.4, 1.0 Hz, 1H), 7.25 (d, J=9.2 Hz, 1H), 7.31 (d,J=3.1 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.74 (dd, J=8.5, 1.7 Hz, 1H),8.08 (d, J=9.5 Hz, 1H), 8.14 (d, J=1.4 Hz, 1H) ppm. MS (DCI/NH₃): m/z321 (M+H)⁺.

Example 9C5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indolefumarate

The product of Example 9B (240 mg, 0.75 mmol) was treated with fumaricacid (93 mg, 0.8 mmol) in EtOAc/EtOH (v. 1:1, 10 mL) at ambienttemperature for 15 h. The title compound was obtained as solid (247 mg,yield, 72%). ¹H NMR (300 MHz, CD₃OD) δ 1.88-2.22 (m, 3H), 2.31-2.47 (m,1H), 2.59-2.68 (m, 1H), 3.23-3.50 (m, 5H), 3.89-4.00 (m, 1H), 5.49-5.57(m, 1H), 6.56(dd, J=3.0, 1.0 Hz, 1H), 6.69 (s, 2H), 7.29-7.35 (m, 2H),7.52 (dt, J=8.5, 1.0 Hz, 1H), 7.74 (dd, J=8.5, 1.7 Hz, 1H), 8.12-8.17(m, 2H) ppm. MS (DCI/NH₃): m/z 321 (M+H)⁺. Anal. Calcd. forC₁₉H₂₀N₄O.1.1 C₄H₄O₄.0.4 H₂O:C, 61.73; H, 5.58; N, 12.31. Found: C,61.67; H, 5.52; N, 12.33.

Example 105-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-3-methyl-1H-indoleExample 10A3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

Under N₂, a mixture of 5-bromo-3-methyl-1H-indole (Aldrich, 1.05 g, 5mmol), bis(pinacolato)diboron (Aldrich, 1.40 g, 5.5 mmol),PdCl₂(dppf).CH₂Cl₂ (Aldrich, 122 mg, 0.15 mmol) and KOAc (Aldrich, 1.47g, 15 mmol) in DMSO (20 mL) was stirred at 90° C. for 1 h. The reactionwas monitored with TLC. After the reaction was complete, it was thendiluted with EtOAc (100 mL) and washed with brine (3×10 mL). The organicsolution was then concentrated and the title compound was purified byflash chromatography (SiO₂, Hexane:EtOAc, 80:20, R_(f). 0.70) as solid(510 mg, yield, 40%). ¹H NMR (300 MHz, CDCl₃) δ 1.38 (s, 12H), 2.35 (s,3H), 6.98 (s, 1H), 7.34 (dd, J=8.1, 0.7, Hz, 1H), 7.65 (dd, J=8.1, 1.0Hz, 1H), 8.12 (s, 1H) ppm. MS (DCI/NH₃): m/z 258 (M+H)⁺.

Example 10B5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-3-methyl-1H-indole

The product of Example 10A (240 mg, 1 mmol) coupled with the product ofExample 9A (250 mg, 1 mmol) according to the procedure in Example 8A,The title product was purified by preparative HPLC (Gilson, column,Symmetry® C-8 7 pm, 40×100 mm. Eluting Solvent, MeCN/H₂O (with 0.2% v.TFA) (v. 90/10 to 10/90 over 20 min. flow rate, 75 mL/min., uv, 250 nm)as solid (40 mg, yield, 12%). ¹H NMR (300 MHz, CD₃OD) δ 1.50-1.64 (m,1H), 1.69-1.92 (m, 2H), 2.01-2.14 (m, 1H), 2.29-2.35 (m,1H), 2.37 (s,3H), 2.81-3.04 (m, 5H), 3.43-3.55 (m,1H), 5.27-5.34 (m, 1H), 7.06 (d,J=1.4 Hz, 1H), 7.24 (d, J=9.2 Hz,1H), 7.44 (dd, J=8.5, 0.7 Hz, 1H), 7.71(dd, J=8.8, 2.0, Hz, 1H), 8.07-8.12 (m, 2H) ppm. MS (DCI/NH₃): m/z 335(M+H)⁺.

Example 10C5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-3-methyl-1H-indole fumarate

The product of Example 10B (40 mg, 0.12 mmol) was treated with fumaricacid (23 mg, 0.2 mmol) in EtOAc/EtOH (v.1:1, 5 mL) at ambienttemperature for 10 h. The title compound was obtained as solid (40 mg,yield, 62%). ¹H NMR (300 MHz, CD₃OD) δ 1.90-2.24 (m, 3H), 2.33-2.48 (m,4H), 2.61-2.68 (m,1H), 3.22-3.53 (m, 5H), 3.93-4.03 (m,1H), 5.51-5.58(m, 1H), 6.70 (s, 3.6H), 7.08 (d, J=1.0 Hz,1H), 7.32 (d, J=9.5 Hz, 1H),7.45 (d, J=8.5 Hz, 1H), 7.72 (dd, J=8.8, 1.7 Hz, 1H), 8.10 (d, J=1.7 Hz,1H), 8.17 (d, J=9.5 Hz,1H) ppm. MS (DCI/NH₃): m/z 335 (M+H)⁺. Anal.Calculated for C₂₀H₂₂N₄O.1.8 C₄H₄O₄:C, 60.13; H, 5.42; N, 10.31. Found:C, 60.02; H, 5.53; N, 10.27.

Example 115-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indoleExample 11A (3R)-3-[(5-bromopyrimidin-2-yl)oxy]quinuclidine

The product of Example 4A (508 mg, 4 mmol) was coupled with5-bromo-2-iodo-pyrimidine (Aldrich, 1.42 g, 5 mmol) according to theprocedure of Example 7A. The title compound was purified bychromatography (SiO₂, CH₂Cl₂:MeOH: NH₃.H₂O, 90:10:1, R_(f). 0.40) assolid (760 mg, yield, 67%). ¹H NMR (300 MHz, CD₃OD) δ 1.54-1.68 (m, 1H),1.68-1.95 (m, 2H), 2.03-2.16 (m, 1H), 2.24-2.33 (m, 1H), 2.82-3.11 (m,5H), 3.41-3.52 (m, 1H), 5.09-5.17 (m, 1H), 8.65 (s, 2H). MS (DCI/NH₃):284 (M+H)⁺286 (M+H)⁺.

Example 11B5-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indole

The product of Example 11A (283 mg, 1 mmol) was coupled with5-indolylboronic acid (Aldrich, 193 mg, 1.2 mmol) according to theprocedure of Example 3A. The title product was purified by preparativeHPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent,MeCN/H₂O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min. flow rate,75 mL/min., uv, 250 nm) as solid (40 mg, yield, 12%). ¹H NMR (300 MHz,CD₃OD) δ 1.50-1.63 (m, 1H), 1.67-1.93 (m, 2H), 2.04-2.17 (m, 1H),2.24-2.31 (m, 1H), 2.75-3.05 (m, 5H), 3.38-3.48 (m, 1H), 5.14-5.21 (m,1H), 6.53 (dd, J=3.1, 0.7 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 7.35 (dd,J=8.5, 1.7 Hz,1H), 7.51 (dt, J=8.5, 0.7 Hz,1H), 7.80 (dd, J=1.7, 0.7 Hz,1H), 8.82 (s, 2H) ppm. MS (DCI/NH₃): m/z 321 (M+H)⁺.

Example 11C5-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indolehemifumarate

The product of 11 B (40 mg, 0.12 mmol) was treated with fumaric acid (12mg, 0.1 mmol) in EtOAc/EtOH (v.1:1, 3 mL) at ambient temperature for 10h. The title compound was obtained as solid (42 mg, yield, 88%). ¹H NMR(300 MHz, CD₃OD) 61.72-2.10 (m, 3H), 2.20-2.34 (m, 1H), 2.43-2.51 (m,1H), 3.04-3.43 (m, 5H), 3.65-3.76 (m, 1H), 5.28-5.36 (m, 1H), 6.52 (dd,J=3.1, 1.1 Hz, 1H), 6.67 (s, 1H), 7.30 (d, J=3.1 Hz, 1H), 7.35 (dd,J=8.5, 1.7 hz, 1H), 7.51 (dt, J=8.5, 0.7 Hz, 1H), 7.80 (dd, J=1.7, 0.7Hz, 1H), 8.84 (s, 2H) ppm. MS (DCI/NH₃): m/z 321 (M+H)⁺. Anal. Calcd.for C₁₉H₂₀N₄O.0.6 C₄H₄O₄:C, 65.90; H, 5.79; N, 14.36. Found: C, 65.65;H, 5.24; N, 14.41.

Example 124-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indoleExample 12A4-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indole

The product of Example 11A (170 mg, 0.6 mmol) was coupled with4-(4,4,5,5-tetra-methyl-[1,3,2]dioxaborolan-2-yl)-1H-indole ((ref.WO02055517, 146 mg, 0.6 mmol) according to the procedure in Example 8A.The title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.10) as a solid (76 mg, yield,40%). ¹H NMR (300 MHz, CD₃OD) δ 1.50-1.64 (m, 1H), 1.67-1.93 (m, 2H),2.05-2.19 (m, 1H), 2.25-2.33 (m, 1H), 2.73-3.12 (m, 5H), 3.39-3.50 (m,1H), 5.17-5.25 (m, 1H), 6.55 (dd, J=3.4, 1.0 Hz, 1H), 7.11 (dd, J=7.1,1.0, Hz, 1H), 7.23 (t, J=8.1 Hz,1H), 7.35 (d, J=3.1 Hz,1H), 7.44-7.49(m,1H), 8.85 (s, 2H) ppm. MS (DCI/NH₃): m/z 321 (M+H)⁺.

Example 12B4-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indolefumarate

The product of Example 12A (76 mg, 0.24 mmol) was treated with fumaricacid (29 mg, 0.25 mmol) in EtOAc/EtOH (v.1:1, 4 mL) at ambienttemperature for 10 hours. The title compound was obtained as solid (94.6mg, yield, 90%). ¹H NMR (300 MHz, CD₃OD) δ 1.88-2.21 (m, 3H), 2.33-2.48(m,1H), 2.59-2.66 (m, 1H), 3.22-3.50 (m, 5H), 3.84-3.95 (m,1H),5.41-5.49 (m,1H), 6.55 (dd, J=3.4, 1.0 Hz,1H), 6.68 (s, 2H), 7.11 (dd,J=7.5, 1.0 Hz, 1H), 7.24 (t, J=8.1 Hz,1H), 7.36 (d, J=3.1 Hz, 1H), 7.48(dt, J=8.1, 0.7 Hz, 1H), 8.89 (s, 2H) ppm. MS (DCI/NH₃): m/z 321 (M+H)⁺.Anal. Calculated for C₁₉H₂₀N₄O.C₄H₄O₄:C, 63.29; H, 5.54; N, 12.84.Found: C, 62.95; H, 5.85; N, 12.61.

Example 135-{2-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indoleExample 13A (3R)-1-azabicyclo[2.2.2]oct-3-yl benzoate (L)-tartrate

(+/−)-3-Quinuclidinol benzoate (Sigma, 17.9 g, 77.5 mmol) was treatedwith L-tartaric acid (Aldrich, 99% ee, 11.63 g, 77.5 mmol) in EtOH (80%,222 mL) at ambient temperature for 1 week. The white solid was filteredoff and dried under reduced pressure. 6.5 g of 3-(R)-quinuclidinolbenzoate·(L)-tartrate was obtained with ˜80% ee (assayed by HPLC. HPLCconditions: chiralpak AD column 25 cm×4 mm ID. solvent,EtOH:hexanes=15:85. flow rate, 1 mL/min. uv, 220 nm. Retention time:(S)-3-quinuclidinol benzoate, 7.87 min; (R)-3-quinuclidinol benzoate13.3 min.) Recrystallization of the above solid in EtOH (80%, 35 mL)gave the title product (4.5 g, yield, 15%, >98% ee). MS (DCI/NH₃) m/z232 (M+H)⁺.

Example 13B (3R)-quinuclidin-3-ol

The product of the Example 13A (4.5 g, 11.8 mmol) was treated withHydrolysis was NaOH (15%, 40 mL) MeOH (40 mL)at 50° C. for 10 h. Themethanol was removed under reduced pressure and the residue wasextracted with chloroform (4×80 mL). The extracts were combined anddried over MgSO₄ (anhydrous). The drying agents were filtered off andthe filtrate was concentrated to give the title product as white solid(1.35 g, yield, 0.90%). MS (DCI/NH₃) m/z 128 (M+H)⁺.

Example 13C (3S)-1-azabicyclo[2.2.2]oct-3-yl benzoate (D)-tartrate

The mother liquid of Example 13A was combined and concentrated underreduced pressure. The residue was then treated with NaOH (1 N, 50 mL) atroom temperature for 30 min. It was extracted with chloroform (3× mL)The extracts were combined and dried (MgSO₄). The drying agents werefiltered off. The filtrates was concentrated to give 3-quinuclidinolbenzoate (15.25 g, 66 mmol) It was then treated with (D)-tartaric acid(Aldrich, 97% ee, 9.9 g, 66 mmol,) in EtOH (80%, 190 ml) at roomtemperature for 3 days according to the procedure of Example 1A. Thetitle product was obtained (7.0 g, yield, 28%, 92.3% ee).

Example 13D (3S)-quinuclidin-3-ol

The product of Example 13C (7.0 g, 18.4 mmol) was treated with NaOH(aqueous) according to the procedure of Example 1B. The title productwas obtained as white solid (2.0 g, yield, 86% ) MS (DCI/NH₃) m/z 128(M+H)⁺.

Example 13E (3S)-3-[(5-bromopyrimidin-2-yl)oxy]quinuclidine

The product of Example 13 (508 mg, 4 mmol) was coupled with2-iodo-5-bromo-pyrimidine (1.42 g, 5 mmol) according to the procedure ofExample 7A. The title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.20) as solid (780 mg, yields,69%)as a solid. ¹H NMR (300 MHz, CD₃OD) δ 1.47-1.61 (m, 1H), 1.63-1.90(m, 2H), 1.96-2.12 (m, 1H), 2.19-2.27 (m, 1H), 2.73-3.03 (m, 5H),3.33-3.45 (m, 1H), 5.05-5.14 (m, 1H), 8.64 (s, 2H) ppm. MS (DCI/NH₃):284 (M+H)⁺286 (M+H)⁺.

Example 13F5-{2-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indole

The product of Example 13E (283 mg, 1 mmol) was coupled with5-indolylboronic acid (193 mg, 1.2 mmol) according to the procedure ofExample 3A, The title product was purified by preparative HPLC (Gilson,column, Symmetry®) C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H₂O (with0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv,250 nm) as solid (120 mg, yield, 38%). ¹H NMR (300 MHz, CD₃OD) δ1.50-1.63 (m, 1H), 1.66-1.92 (m, 2H), 2.03-2.18 (m, 1H), 2.24-2.32 (m,1H), 2.75-3.07 (m, 5H), 3.38-3.49 (m, 1H), 5.13-5.21 (m, 1H), 6.53 (dd,J=3.0, 0.7 Hz, 1H), 7.30 (d, J=3.4 Hz, 1H), 7.35 (dd, J=8.5, 1.7 Hz,1H), 7.51 (dt, J=9.2, 0.7 Hz, 1H), 7.80 (dd, J=1.7, 0.7 Hz, 1H), 8.81(s, 2H) ppm. MS (DCI/NH₃): m/z 321 (M+H)⁺.

Example 13G5-{2-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indolehemifumarate

The product of Example 13F (120 mg, 0.38 mmol) was treated with fumaricacid (44 mg, 0.38 mmol) in EtOAc/EtOH (v. 1:1, 10 mL). The titlecompound was obtained as solid (123 mg, yield, 84%). ¹H NMR (300 MHz,CD₃OD) 61.75-2.13 (m, 3H), 2.22-2.37 (m, 1H), 2.46-2.54 (m, 1H),3.03-3.45 (m, 5H), 3.68-3.79 (m, 1H), 5.30-5.38 (m, 1H), 6.52 (dd,J=3.1, 1.1 Hz, 1H), 6.67 (s, 1.2H), 7.30 (d, J=3.1 Hz, 1H), 7.35 (dd,J=8.5, 1.7 Hz, 1H), 7.51 (dt, J=8.5, 0.7 Hz, 1H), 7.80 (dd, J=1.7, 0.7Hz, 1H), 8.82 (s, 2H) ppm. MS (DCI/NH₃): m/z 321 (M+H)⁺. Anal.Calculated for C₁₉H₂₀N₄O.0.6 C₄H₄O₄:C, 65.90; H, 5.79; N, 14.36. Found:C, 65.62; H, 5.76; N, 14.40.

Example 145-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-3-methyl-1H-indazoletrifluoroacetate

The product of Example 1A (200 mg, 0.61 mmol) was coupled witht-Butyl-(3-Methyl-5-trimethylstannanyl-indazole)-1-carboxylate (ref. US2003199511, 294 mg, 1 mmol) according to the procedure of Example 2B.The title product was purified by preparative HPLC (Gilson, column,Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H₂O (with 0.2% v.TFA) (v. 90/10 to 10/90 over 20 min. flow rate, 75 mL/min., uv, 250 nm)as solid (70 mg, yield, 26%). ¹H NMR (300 MHz, CD₃OD) δ 1.85-2.13 (m,3H), 2.22-2.37 (m, 1H), 2.46-2.50 (m, 1H), 2.58 (s, 3H), 3.23-3.45 (m,5H), 3.78-3.86 (m, 1H), 4.90-5.00 (m, 1H), 7.07 (dt, J=8.8, 2.0 Hz, 2H),7.50 (d, J=8.8 Hz, 1H), 7.61-7.68 (m, 3H), 7.85 (s, 1H) ppm. MS(DCI/NH₃): m/z 334 (M+H)⁺. Anal. Calculated for C₂₁H₂₃N₃O.1.0CF₃CO₂H.0.5 H₂O:C, 60.52; H, 5.52; N, 9.21. Found: C, 60.79; H, 5.39; N,9.17.

Example 156-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1,3-benzothiazol-2-amineExample 15A 3-[(4′-nitro-1,1 ′-biphenyl-4-yl)oxy]quinuclidine

3-Quinuclidinol (Aldrich, 0.51 g, 4 mmol) coupled with4′-nitro-1,1′-biphenyl-4-ol (TCI, 0.43 g, 2 mmol) with DIAD(di-isopropyl azadicarboxylate, Aldrich, 0.81 g, 4 mmol) and Ph₃P(Aldrich, 1.04 g, 4 mmol) in THF (anhydrous, Aldrich, 40 mL) at ambienttemperature for two days. The reaction mixture was concentrated. Thetitle product was purified by chromatography (SiO₂, CH₂Cl₂:MeOH:NH₃.H₂O,90:10:1, R_(f). 0.20) as solid (400 mg, yield, 62%). ¹H NMR (300 MHz,CD₃OD) δ 1.45-1.57 (m, 1H), 1.63-1.91 (m, 2H), 1.97-2.12 (m, 1H),2.17-2.24 (m, 1H), 2.66-3.00 (m, 5H), 3.30-3.41 (m, 1H), 4.56-4.64 (m,1H), 7.05 (dt, J=8.8, 2.6 Hz, 2H), 7.68 (dt, J=9.2, 2.6 Hz, 2H), 7.82(dt, J=8.8, 2.7 Hz, 2H), 8.28 (dt, J=8.8, 2.8 Hz, 2H) ppm. MS (DCI/NH₃)m/z 325 (M+H)⁺.

Example 15B 4′-(1-azabicyclo[2.2.2]oct-3-yloxy)-1,1′-biphenyl-4-amine

The product of Example 15A (300 mg, 0.92 mmol) was treated with Pd/C(Aldrich, wt.10%, 30 mg) in methanol (20 mL) under H₂ at ambienttemperature for 30 min. After the reaction was complete, the catalystwas removed through a short column of diatomaceous earth. The filtratewas concentrated under reduced pressure to provide the title compound(200 mg, yield, 74%). ¹H NMR (300 MHz, CD₃OD) δ 1.44-1.58 (m, 1H),1.63-1.89 (m, 2H), 1.99-2.13 (m, 1H), 2.15-2.23 (m, 1H), 2.72-3.04 (m,5H), 3.29-3.39 (m, 1H), 4.50-4.58 (m, 1H), 6.77 (dt, J=8.8, 2.5 Hz, 2H),6.91 (dt, J=8.8, 2.4 Hz, 2H), 7.32 (dt, J=8.5, 2.5 Hz, 2H), 7.43(dt,J=9.2, 2.8 Hz, 2H) ppm. MS (DCI/NH₃) m/z 295 (M+H)⁺.

Example 15C6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1,3-benzothiazol-2-amine

The product of Example 15B (200 mg, 0.68 mmol) and KSCN (Aldrich, 140mg, 1.52 mmol) were dissolved in HOAc (5 mL). Bromine [Aldrich, 99%, 40μL, 0.76 mmol, in HOAc (1 mL) was added slowly to the above solutionover 5 min. The mixture was stirred at ambient temperature foradditional 1 h. and then quenched with aqueous NaOH (10%, 20 mL) at5-10° C. It was then extracted with CHCl₃/^(i)PrOH (v. 10: 1, 2×50 mL).The extracts were combined and concentrated under reduced pressure. Thetitle compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:1, R_(f). 0.10) as solid (140 mg, yield,59%). ¹H NMR (300 MHz, CD₃OD) δ 1.27-1.37 (m, 1H), 1.51-1.72 (m, 2H),1.79-1.88 (m, 1H), 2.02-2.07 (m, 1H), 2.51-2.84 (m, 5H), 3.21-3.39 (m,1H), 4.45-4.52 (m, 1H), 6.97(d, J=8.8 Hz, 2H), 7.35 (d, J=8.5 Hz, 7.45(dd, J=8.5, 2.1 Hz, 1H), 7.55 (d, J=8.5, 2H), 7.90 (d, J=2.0 Hz, 1H)ppm. MS (DCI/NH₃) m/z 352 (M+H)⁺.

Example 15D6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1,3-benzothiazol-2-aminebistrifluoroacetate

The product of Example 15C (140 mg, 0.4 mmol) was treated withtrifluroacetic acid (Aldrich, 99%, 114 mg, 80 μL, 1 mmol) in ^(i)PrOH (5mL) at ambient temperature for 15 h. The title compound was obtained assolid (90 mg, yield, 39%). ¹H NMR (300 MHz, DMSO-D₆) δ 1.75-2.16 (m,3H), 2.30-2.52 (m, 2H), 3.03-3.45 (m, 5H), 3.75-3.82 (m, 1H), 4.78-4.85(m, 1H), 7.05 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.5 Hz, 1H), 7.50 (dd,J=8.5, 2.1 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.76 [s(broad.), 2H], 7.96(d, J=1.7 Hz, 1H) ppm. MS (DCI/NH₃): m/z 352 (M+H)⁺. Anal. Calculatedfor C₂₀H₂₁N₃OS.2.08 CF₃CO₂H C, 49.30; H, 3.95; N, 7.14. Found: C, 49.70;H, 3.42; N, 7.03.

Example 16 N-[4-(3-methyl-1H-indazol-5-yl)phenyl1quinuclidin-3-amineExample 16A N-(4-iodophenyl)quinuclidin-3-amine

3-Quinuclidinone hydrochloride (Aldrich, 3.22 g, 20 mmol) was treatedwith 4-iodo-aniline (Aldrich, 2.19 g, 10 mmol), Na₂SO₄ (anhydrous,Aldrich, 7.40 g, 50 mmol) and NaBH(OAc)₃ (Aldrich, 3.16 g, 15 mmol) inHOAc (25 mL) at ambient temperature for 15 h. After the reaction wascomplete, the reaction mixture was slowly poured into a flask containing75 mL of saturated NaHCO₃ and stirred for 20 min. It was then extractedwith EtOAc (3×100 mL). The extracts were combined and washed with brine(2×20 mL). The organic solution was concentrated under reduced pressureand the title compound was purified by chromatography (SiO₂,CH₂Cl₂:MeOH:NH₃.H₂O, 90:10:2, R_(f). 0.10) as oil (3.24 g, yield, 98%).¹H NMR (300 MHz, CD₃OD,) δ 1.70-1.81 (m, 1H), 1.93-2.04 (m, 2H),2.08-2.24 (m, 2H), 2.89 (ddd, J=12.9, 5.1, 2.7 Hz, 1H), 3.12-3.28 (m,4H), 3.64 (ddd, J=12.9, 9.5, 2.4 Hz, 1H), 3.79-3.85 (m, 1H), 6.46 (dt,J=9.0, 2.7 Hz, 2H), 7.39 (dt, J=9.1, 2.7 Hz, 2H) ppm. MS (DCI/NH₃) m/z329 (M+H)⁺.

Example 16B N-[4-(3-methyl-1H-indazol-5-yl)phenyl]quinuclidin-3-aminetrifluoroacetate

The product of Example 16A (200 mg, 0.61 mmol) was coupled witht-Butyl-(3-Methyl-5-trimethylstannanyl-indazole)-1-carboxylate (ref. US2003199511, 294 mg, 1 mmol) according to the procedure of Example 2B.The title product was purified by preparative HPLC (Gilson, column,Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H₂O (with 0.2% v.TFA) (v.90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm)as solid (28 mg, yield, 10%). ¹H NMR (300 MHz, CD₃OD) δ 1.85-1.96 (m,1H), 2.08-2.15 (m, 2H), 2.24-2.40 (m, 2H), 2.59 (s, 3H), 3.02-3.15 (m,1H), 3.20-3.45 (m, 4H), 3.78-3.88 (m, 1H), 3.98-4.06 (m, 1H), 6.77 (dt,J=8.8, 2.0 Hz, 2H), 7.46-7.52 (m, 3H), 7.59 (dd, J=8.9, 1.6 Hz, 1H),7.78 (s,1H) ppm. MS (DCI/NH₃): m/z 333 (M+H)⁺. Anal. Calculated forC₂₁H₂₄N₄.1.25 CF₃CO₂H: C, 59.43; H, 5.36; N, 11.80. Found: C, 59.20; H,4.96; N, 11.62.

Example 17 Determination of Biological Activity DETERMINATION OFBIOLOGICAL ACTIVITY

To determine the effectiveness of representative compounds of thisinvention as α7 nAChRs, the compounds of the invention were evaluatedaccording to the [3H]-methyllycaconitine (MLA) binding assay andconsidering the [3H]-cytisine binding assay, which were performed asdescribed below.

[3H]-Cytisine Binding

Binding conditions were modified from the procedures described inPabreza LA, Dhawan, S, Kellar K J, [³H]-Cytisine Binding to NicotinicCholinergic Receptors in Brain, Mol. Pharm. 39: 9-12, 1991. Membraneenriched fractions from rat brain minus cerebellum (ABS Inc.,Wilmington, Del.) were slowly thawed at 4° C., washed and resuspended in30 volumes of BSS-Tris buffer (120 mM NaCl/5 mM KCl/2 mM CaCl₂/2 mMMgCl₂/50 mM Tris-Cl, pH 7.4, 4° C.). Samples containing 100-200 pg ofprotein and 0.75 nM [3H]-cytisine (30 C_(i)/mmol; Perkin Elmer/NEN LifeScience Products, Boston, Mass.) were incubated in a final volume of 500μL for 75 minutes at 4° C. Seven log-dilution concentrations of eachcompound were tested in duplicate. Non-specific binding was determinedin the presence of 10 μm (−)-nicotine. Bound radioactivity was isolatedby vacuum filtration onto prewetted glass fiber filter plates(Millipore, Bedford, Mass.) using a 96-well filtration apparatus(Packard Instruments, Meriden, Conn.) and were then rapidly rinsed with2 mL of ice-cold BSS buffer (120 mM NaCl/5 mM KCl/2 mM CaCl₂/2 mMMgCl₂). Packard MicroScint-20® scintillation cocktail (40 μL) was addedto each well and radioactivity determined using a Packard TopCount®instrument. The IC₅₀ values were determined by nonlinear regression inMicrosoft Excel® software. K_(i) values were calculated from the IC₅₀susing the Cheng-Prusoff equation, where K_(i)=IC₅₀/1 +[Ligand]/K_(D)].

[3H1-Methyllycaconitine (MLA) bindinq

Binding conditions were similar to those for [3H]-cytisine binding.Membrane enriched fractions from rat brain minus cerebellum (ABS Inc.,Wilmington, Del.) were slowly thawed at 4° C., washed and resuspended in30 volumes of BSS-Tris buffer (120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mMMgCl₂, and 50 mM Tris-Cl, pH 7.4, 22° C.). Samples containing 100-200 μgof protein, 5 nM [3H]-MLA (25 C_(i)/mmol; Perkin Elmer/NEN Life ScienceProducts, Boston, Mass.) and 0.1% bovine serum albumin (BSA, Millipore,Bedford, Mass.) were incubated in a final volume of 500 μL for 60minutes at 22° C. Seven log-dilution concentrations of each compoundwere tested in duplicate. Non-specific binding was determined in thepresence of 10 μM MLA. Bound radioactivity was isolated by vacuumfiltration onto glass fiber filter plates prewetted with 2% BSA using a96-well filtration apparatus (Packard Instruments, Meriden, Conn.) andwere then rapidly rinsed with 2 mL of ice-cold BSS. PackardMicroScint-20® scintillation cocktail (40 μL) was added to each well andradioactivity was determined using a Packard TopCount® instrument. TheIC₅₀ values were determined by nonlinear regression in Microsoft Excel®software. K_(i) values were calculated from the IC₅₀s using theCheng-Prusoff equation, where K_(i)=IC₅₀/1 +[Ligand]/K_(D)].

Compounds of the invention had K_(i) values of from about 1 nanomolar toabout 10 micromolar when tested by the MLA assay, many having a K_(i) ofless than 1 micromolar. [3H]-Cytisine binding values of compounds of theinvention ranged from about 50 nanomolar to at least 100 micromolar. Thedetermination of preferred compounds typically considered the K_(i)value as measured by MLA assay in view of the K_(i) value as measured by[3H]-cytisine binding, such that in the formulaD=K_(i 3H-cytisine)/K_(i MLA), D is about 50. Preferred compoundstypically exhibited greater potency at α7 receptors compared to α4β2receptors.

Compounds of the invention are α7 nAChRs ligands that modulate functionof α7 nAChRs by altering the activity of the receptor. The compounds canbe inverse agonists that inhibit the basal activity of the receptor orantagonists that completely block the action of receptor-activatingagonists. The compounds also can be partial agonists that partiallyblock or partially activate the α7 nAChR receptor or agonists thatactivate the receptor.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

1. A compound of the formula (I):

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,wherein: n is 0, 1, or 2; X is selected from the group consisting of O,S, and NR¹; Ar¹ is a 6-membered aromatic ring containing 0, 1, 2, 3, or4 nitrogen atoms; Ar² is a group of the formula:

Y¹ is independently selected from O, S, N(R²), and C(R³); Y² and Y³ areeach independently selected from the group consisting of N and C(R³); R¹and R² at each occurrence are each independently selected from the groupconsisting of hydrogen and alkyl; R³ at each occurrence is independentlyselected from the group consisting of hydrogen, halogen, alkyl, aryl,—OR⁴, —NR⁵R⁶; R⁴ is selected from the group consisting of hydrogen,alkyl, aryl, alkylcarbonyl, and arylcarbonyl; and R⁵ and R⁶ at eachoccurrence are each independently selected from the group consisting ofhydrogen, alkyl, aryl, alkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,and arylcarbonyl, provided that one of R⁵ and R⁶ is hydrogen or alkyl.2. The compound of claim 1, wherein Ar¹ is a group of the formula:

wherein: X¹, X², X³, and X⁴ are each independently selected from thegroup consisting of N and —CR¹⁰; and R¹⁰ at each occurrence isindependently selected from the group consisting of hydrogen and alkyl.3. The compound of claim 1, wherein Ar¹ is selected from the groupconsisting of:


4. The compound of claim 1, wherein Ar² is selected from the groupconsisting of:


5. The compound of claim 1, or a pharmaceutically acceptable salt,ester, amide, or prodrug thereof, selected from the group consisting of:3-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;5-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-1H-indole;6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;2-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;5-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indole;4-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indole;5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole;5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-3-methyl-1H-indole;5-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indole;4-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indole;5-{2-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-indole;5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-3-methyl-1H-indazole;6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1,3-benzothiazol-2-amine;and N-[4-(3-methyl-1H-indazol-5-yl)phenyl]quinuclidin-3-amine.
 6. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 in combination with a pharmaceuticallyacceptable carrier.
 7. A method of selectively modulating the effects ofα7 nicotinic acetylcholine receptors in a mammal comprisingadministering an effective amount of a compound of claim
 1. 8. A methodof treating or preventing a condition or disorder selected from thegroup consisting of attention deficit disorder, attention deficithyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitiveimpairment, senile dementia, AIDS dementia, Pick's Disease, dementiaassociated with Lewy bodies, dementia associated with Down's syndrome,amyotrophic lateral sclerosis, Huntington's disease, diminished CNSfunction associated with traumatic brain injury, acute pain,post-surgical pain, chronic pain, inflammatory pain, neuropathic pain,infertility, need for new blood vessel growth associated with woundhealing, need for new blood vessel growth associated withvascularization of skin grafts, and lack of circulation, moreparticularly circulation around a vascular occlusion, comprising thestep of administering a compound of claim
 1. 9. The method according toclaim 1, wherein the condition or disorder is selected from the groupconsisting of a cognitive disorder, neurodegeneration, andschizophrenia.
 10. The method according to claim 1, further comprisingadministering a compound of claim 1 in combination with an atypicalantipsychotic.